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G-Protein Receptors
Uni of Notts, Signalling & Metabolic Regulation, year 2, topic 1
| Question | Answer |
|---|---|
| Standard GCPR structure | 7 cylindrical transmembrane α-helices, domains can bind ligands inside or outside the cell. Binds to an intracellular G-protein |
| Large heterotrimeric G-proteins | Composed of Gαβγ subunits, bound to membrane with attached lipid tails. Gα binds GTP, intrinsic GTPase activity to switch the protein on & off. β & γ dimerise to form a stable complex which can dissociate & modulate effectors. |
| Functional classes of Gα subunits (4) | Gs - Stimulates cAMP pathway by activating adenyl cyclase Gi - Inhibits cAMP pathway by inhibiting adenyl cyclase Gq - Activates phospholipase Cβ to hydrolyse PIP2 to DAG & IP3 |
| How G-proteins switch themselves off | Domains have intrinsic GTPase activity but often need to recruit enzymes |
| GEFs | Guanine nucleotide Exchange Factors. Swap GDP for GTP. Monomeric use cytosolic proteins as GEFs but large trimeric have activated receptors which act as GEFs |
| GAPs | GTPase Activation Factor. Allow G-proteins to hydrolyse GTP |
| GDIs | Guanine nucleotide Dissociation Inhibitors. Stabilise the complex to prevent reactivation of G-proteins |
| Small monomeric G-proteins Monomeric G-protein superfamilies (5) | Simple GTPase accessory proteins structurally similar to Gα domains Ras (growth), rho (cytoskeleton), rab (vesicles), ran (nuclear transport), arf (membranes) |
| Permanent inactivation of G-proteins: GRK | GPCR-Kinase, serine/threonine activity. Phosphorylates cytosolic tail (or 3rd loop). Decreases G-protein activity & increases affinity to arrestin |
| Permanent inactivation of G-proteins: Arrestin & clatherin pit | Arrestin binds to phosphorylated cytosolic tail, sterically hinders ligand binding & acts as a clatherin adaptor, recruits β-clatherin pit which marks the GCPR for exocytosis |
| Permanent inactivation of G-proteins: Final fate of GCPRs | Proteins either degraded (polyubiquitylation) or moved to the cytosol for different regulatory pathways but become regular receptors since they can now signal without G-proteins |
| RGS proteins | Regulators of G-protein Signalling proteins. GAPs. Don't have intrinsic GTPase activity but bind to conserved surface of Gα. Positions Arg & Glu to stabilise the transition state between GTP & GDP |
| Constitutive activity | Ability of a receptor (most often G-proteins) to have base level of activity without the binding of ligands (i.e., spontaneously forms an active conformation) |
| Why GCPRs are more like rheostats than molecular switches | Controls signal by varying the level of signalling. Rather than switching the signal on or off, ligands only increase of decrease relative to base activity |
| Full agonists | Complete maximum receptor stimulation |
| Partial agonists | Increases activity but can't reach maximum even in saturating concentrations |
| Neutral agonists | Antagonists. No affect on signalling (keeps it at base level) but prevents the binding of other ligands |
| Inverse agonists | Reduces the level of constitutive activity below the level of signalling of a receptor with no bound ligands |
| Mechanical factors affecting G-protein activity (4) | Localisation: Determines receptor-effector proximity & signal type Membrane composition: Affects coupling with protein-lipid interactions Dimerization: Novel or cooperative signalling Oligomerisation: Large receptor networks, cross-talk, finetuning |
| Odorants | Low molecular weight hydrophobic organic molecules with diverse structures & functional groups which can trigger olfactory receptors |
| Process of odour detection | Odorants dissolve into mucus & binds to modified cilia GCPRs on olfactory epithelium. G-olf activates adenylyl cyclase to produce cAMP & trigger action potential. This travels along a sensory axon to the olfactory bulb |
| Organising principles | Cilia only expresses 1 type of Olfactory Receptor (OR) to innervate the same glomerulus on the olfactory bulb A single receptor can recognise multiple odorants, each affecting the constitutive activity differently so patterns of neural activity form |
| Fascial convergence | Signals from the same receptor type don't travel independently, they migrate together to the same glomerulus in the olfactory bulb |
| Combinatorial coding | Each odorant binds with different affinities to various receptors causing a pattern of brain activity unique to that molecule to the amygdala (emotions), piriform cortex (identification), & entorhinal cortex (memory) |
| Role of neuropilin1 (NRP1) in olfaction | Expression of this transmembrane protein correlate with cAMP levels. Each sensory neurone express graded amounts. More NRP1 sends the signal to more posterior regions of the bulb |
Created by:
Denny12
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